Organic compounds

ABSTRACT

An oral dosage form comprising fluvastatin and HPMC, which oral dosage form is color-stable upon prolonged periods of storage.

This invention is concerned with formulations for sustained release offluvastatin.

Fluvastatin is a member of a class of drugs commonly referred to as HMGCoA reductase inhibitors (sometimes called “statins”). The statins areused to reduce blood cholesterol levels in patients in need of suchtreatment. The site of action of the statins is the liver. Conventionalrapid release forms of statins, e.g. which release the statin withinabout 2 hours have mild side effects associated with systemic deliveryof the statin. The statins appear to enter systemic circulation becauseof the relatively high concentration of statin entering the liver in arelatively short space of time tends to flood the liver such that someof the statin is not metabolised on the first pass.

Sustained release formulations have been suggested as a means ofpreventing or amelioratiing the side effects associated with systemicentry of the statins—lovastatin, simvastatin and pravastatin (see EP 0375 156).

Several methods of providing sustained release formulations have beenproposed in the art. One such means is to use certain excipients in amatrix which modify the release of an active agent dispersed within saidmatrix. Hydroxypropyl methyl cellulose (HPMC) polymers have beensuggested as release-modifying excipients, either alone or incombination with other materials, in sustained release formulations foruse with a wide variety of active agents including the HMG CoA reductaseinhibitors, see for example U.S. Pat. No. 4,369,172, U.S. Pat. No.4,357,469, U.S. Pat. No. 4,226,849 and U.S. Pat. No. 4,389,393. It isthought that formulations containing HPMC polymers prolong drug releaseby forming a gelatinous matrix upon exposure to the aqueous medium ofthe stomach which prevents or delays ingress of the aqueous medium ofthe stomach into the dosage form and thereby preventing its rapiddisintegration. The gel matrix is thought to form as a result ofhydration of the HPMC polymer. However, the applicant could not find anysuggestion that hydration of the HPMC occurred during storage of oraldosage forms containing HPMC Furthermore, whether hydration occursduring storage or not, none of the aforementioned documents refer to anyinstability problems associated with the use of HPMC and in particularcolour instability.

The applicant was therefore surprised to find that dosage formscomprising HPMC polymers formed gel-like domains upon storage, whichdomains, still more surprisingly were highly coloured. Whereas thisdiscolouration left the dosage forms with an unsightly, uneven mottledappearance, it was of no consequence for the safety and efficacy of thedosage forms. Nevertheless, the mottled appearance may by disturbing topatients and lead to poor patient compliance.

There is a need, therefore to provide dosage forms of fluvastatin forsustained release which are colour-stable upon prolonged periods ofstorage.

In accordance with the present invention there is provided oral dosageforms comprising a mixture of fluvastatin, HPMC polymers and optionallyother pharmaceutical excipients which are colour-stable upon prolongedperiods of storage.

As used hereinbove, “colour-stable” used in connection with oral dosageforms is taken to mean said dosage form in which the mottleddiscolouration hereinabove described is either substantially preventedor is present at levels not detectable by visual inspection, i.e. themottled discolouration is either so faint as to be not apparent or it iscapable of being masked by one or more excipients, e.g. colouringagents.

The presence of the gel-like domains may be detected by visualappearance alone. However, it may also be detected using knownanalytical techniques, for example microcalorimetry. Microcalorimetrymay detect any heat flow, e.g. an exotherm as a result of excipientinteractions, e.g. an exotherm associated with the hydration of HPMC. Itis a characteristic of oral dosage forms of the invention that theydisplay a significant heat flow, i.e. a heat flow of greater than 5micro Watts, e.g. up to 59 micro Watts, more particularly 19 to 59 microWatts over a relatively long period of time, e.g. a period of 48 hours,when subjected to a stress test at 40 degrees centigrade and 75%relative humidity. The stress test may be carried out on an isothermalmicrocalorimeter (CSC Corporation, Provo. Utah) set to 40 degreescentigrade. The oral dosage form may be subjected to an environment of75% relative humidity by, e.g. by preparing minihydrostats using asodium chloride solution inside 250 microlitre polypropylene vialinserts.

As stated hereinabove, colour-stability may be achieved by substantiallypreventing or modulating the formation of HPMC gels. One means ofachieving the object of colour stability may be to reduce the ambientmoisture levels surrounding the oral dosage forms during storage.Applicant has found that oral dosage forms stored under conditions suchthat the relative humidity does not exceed 75%, more preferably no morethan 60%, e.g. 40 to 60% at a temperature of between 25 and 40 degreescentigrade, display a markedly reduced tendency towards discolouration.The type of packaging employed may also reduce discolouration. Whereasconventional blister packaging may be employed, e.g. Triplex TPXblisters, it is preferred to use high density polyethylene (HDPE)bottles. Oral dosage forms as hereinabove described packaged in HDPEbottles may exhibit substantially no discolouration associated with theformation of HPMC gels. Oral dosage forms as hereinabove describedpackaged in HDPE bottles form another aspect of the present invention.

Oral dosage forms according to the invention may be formulated in anyconventional form, e.g. powders, capsules or tablets. Preferred oraldosage forms may be in the form of tablets.

Oral dosage forms hereinabove described may be formed of a granulatedmass comprising fluvastatin, HPMC and optionally other excipientscommonly used in oral dosage forms, e.g. tablets. Surprisingly theapplicant has found that the finer is the mean particle size of thegranulated mass the less intense is the observed mottled disclouration.The applicant believes that the increased colour stability observed asthe mean particle size is decreased may be due to the ability of thefiner granules to form a tighter compact when compressed, therebyreducing the incidence and size of any voids in the compacted mass. Asthe HPMC gels are thought to form in these voids, the smaller theirnumber and/or size, the less tendency there is for gels to form.

Preferred oral dosage forms are tablets which are formed of granulateshaving a mean granulate particle size of less than about 200 microns,e.g. less than 125 microns, more particularly 100 to 125 microns.However, the contribution to the art is the recognition of a correlationbetween granulate size and the incidence and nature of thedisclouration. It follows that the skilled artisan will understand thatfor different excipient mixtures, e.g. amounts of HPMC polymer, theincidence and nature of discolouration may vary within this preferredrange, and in fact discolouration may be absent or visuallyinsignificant outside of the aforementioned ranges. However, with nomore than routine experimentation, the skilled person will be able todetermine a suitable granulate size for a given excipient mixture.Granulates as hereinabove described and oral dosage forms, e.g. tabletsmade therefrom are further aspects of the present invention.

The reduction of moisture levels surrounding the oral dosage forms uponstorage and the use of fine granulates as hereinabove described may beused alone or in combination to achieve the objects of the presentinvention.

As is clear from the definition provided above, an oral dosage form maybe “colour-stable” notwithstanding that it may contain significantamounts of HPMC gel such that the mottled discolouration would be quiteapparent were it not for the presence of a colouring agent masking saiddiscolouration.

Accordingly the invention provides in another of its aspects an oraldosage form comprising a core containing fluvastatin, HPMC andoptionally other excipients, wherein the core contains domains of HPMCgel, and a colouring agent provided in sufficient amounts to mask anymottled discolouration associated with the HPMC gel domains.

Fluvastatin is known to exhibit a tendency towards photodegradation togive a highly coloured degradation product. Whereas this degradation isslight and has no consequence on the efficacy and safety of dosage formscontaining fluvastatin, it is preferred to employ a colouring agent tomask any discolouration associated with this photo-degradation. However,as fluvastatin is typically dispersed essentially uniformly about oraldosage forms any discolouration of this type tends to be rather subtleand uniform. This subtle, dispersed discolouration may therefore bemasked simply by using conventional colouring agents in relatively lowamounts. This is fortunate, as the amounts of colouring agent, e.g. Ironoxides, that may be employed in pharmaceutical formulations are strictlycontrolled by regulatory authorities. For example in the case of ironoxide pigments, the amount of elemental iron acceptable for ingestion iscurrently set at 5 mg/day by the FDA.

However, in contrast to the discolouration associated with thephotodegradation of fluvastatin, the discolouration associated with theformation of the HPMC gel tends to occur in discrete, random domains.The discolouration tends therefore to be more concentrated and thereforemore intense, and patchy and as such is more difficult to mask. As such,conventional colouring agents employed in relatively small amounts donot provide adequate coverage.

The applicant was therefore faced with the problem of how to mask theunsightly, mottled appearance yet at the same time keeping the amountcolouring agent, in particular iron-containing colouring material assmall as possible.

Accordingly, the invention provides in another of its aspects an oraldosage form comprising a core comprising a pharmaceutically activeagent, HPMC and optionally other excipients, and a coating wherein saidcoating comprises a colouring agent present in sufficient amounts tomask any mottled discolouration associated with the formation of HPMCgel.

Whereas the preceding paragraph provides that the colouring agent iscontained in the coating. However, it is within the scope of the presentinvention that the colouring agent may be employed in admixture with theactive agent and other excipients in the core. In such an embodiment acoating would be optional

The colouring agent may be selected from any of those colouring agentsknown in the art, for example pigments, in particular any of thecolouring agents known for use in pharmaceutical preparations aresuitable for use in the present invention, see for example “Handbook ofPharmaceutical Excipients, 2nd Edition (1994), Eds. Wade and Weller”, atpages 130-134. Suitable colouring agents include titanium dioxide, ironoxide (both ferrous and ferric), preferably Fe₂O₃ optionally in hydratedform. In a most preferred embodiment a combination of colouring agentsmay be used e.g., titanium dioxide and iron (II) oxide.

Having regard to the amount of colouring agent that may be employed in aunit dosage form, the maximum amount will be subject to the maximumdaily limits of the given colouring agent permitted by regulatoryauthorities, and may vary below this limit according to the number ofunit dosage forms to be taken per day, e.g. whether the oral dosage formis once- or twice-a-day, and the size of a given unit dosage form. Withthese considerations in mind, the skilled artisan would be able todetermine an appropriate amount of colouring agent to effectively maskany mottled discolouration without undue burden. In a preferredembodiment the colouring agent may constitute up to 73% by weight basedon the total weight of the coating, more particularly 17 to 30%, e.g. 22to 25%. The percentages referred to represent the total colouring agentemployed. i.e. the total colouring agent may be made composed of onecolouring agent, e.g. iron (II) oxide, or a combination, e.g. titaniumdioxide and iron (II) oxide.

Suitable coating materials include those materials conventionally usedin coating tablets, granules and the like. Preferred coating materialsare hydrophilic and permeable to, and/or at least to some extent solublein, water and intestinal fluids. Any of the coating materials, inparticular the elastic coatings described in the art are suitable forthe purposes of the present invention.

Coating materials as hereinabove defined may be used in admixture withother excipients, conventional in coating formulations, for exampletalcum or silicon dioxide, for example synthetic amorphous silicic acidof the Syloid® type (Grace), for example SYLOID 244 FP, or wettingagents, for example the afore-mentioned polyethylene glycols orsorbates.

The coating materials may comprise additional excipients, for exampleplasticisers e.g. triethyl citrate, e.g. Citroflex® (Pfizer), triacetin,various phthalates, e.g. diethyl or dibutyl phthalate, mixed mono- ordi-glycerides of the Myvacet® type (Eastman), for example MYVACET 9-40,the polyethylene glycols mentioned hereinbefore, for example having amolecular weight of approximately from 6000 to 8000, and also ethyleneoxide/propylene oxide block copolymers of the Pluronic® (BASF) orSynperonic® (ICI) type, pulverulent mould release agents, for examplemagnesium trisilicate, starch or synthetic amorphous silicic acid of theSYLOID type, for example SYLOID 244 FP.

Coating weights employed in oral dosage forms according to the inventionmay vary within limits conventional in the art, and typically may be inthe range of about 1 to about 4% by weight based on the total weight ofthe formulation, for example about 3% by weight.

In particularly preferred embodiments, for a 2 mg coated tablet the coatweight is about 2 to 2.5 mg, e.g. 2.44 mg; for a 40 mg coated tablet thecoat weight is about 4.5 to 5.0 mg, e.g 4.86 mg; for 80 mg coatedtablets the coat weight is 9.5 to 10.0 mg, e.g. 9.75 mg; and for 160 mgcoated tablets the coat weight is about 12.0 to 12.5 mg, e.g. 12.3 mg.

Oral dosage forms according to the invention comprise any of thecommercially available hydroxypropylmethyl cellulose polymers that aresuitable for the purpose of providing for sustained release of theactive agent and include any of those materials referred to in EP375156, U.S. Pat. No. 4,369,172, U.S. Pat. No. 4,357,469, U.S. Pat. No.4,226,849 and U.S. Pat. No. 4,389,393 which are incorporated herein byreference.

A preferred HPMC polymer is available from Dow Coming under the tradename METHOCEL. Preferably the HPMC will have a hydroxypropyl (HP) degreeof substitution of up to about 12, i.e. the HPMC will comprise up toabout 12 percent HP functionality. More preferably the HPMC will have HPfunctionality of from 7 to 12 percent, most preferably 7 to 9 percent.The HPMC may have normal viscosity (2.0% HPMC in water) of from about100 to 100,000 centipoise and a number average molecular weight of about20,000 to about 170,000. A particularly preferred HPMC is METHOCEL K100LV, which has a number average molecular weight of about 20,000 to about30,000. Methods of making such HPMC polymers are well known in the art.

HPMC polymers may be employed in amounts sufficient to ensure sustainedrelease of the fluvastatin. By “sustained release” is meant that thefluvastatin is released from the oral dosage form over an extendedperiod of time, e.g. greater than about 6 hours. In a preferred oraldosage form the less than about 80% by weight of the fluvastatin isreleased in the first 8 hours after ingestion of the oral dosage form,with the remaining fluvastatin being release thereafter. In morepreferred compositions, less than about 15% by weight of the fluvastatinis release after 0.5 hour after ingestion, form about 10 to 50% byweight is released within 2 hours after ingestion, and about 40 to 60%is released after 6 hours.

Preferably oral dosage forms according to the invention comprise about15 to about 50% by weight of HPMC, more preferably about 20 to 40%. TheHPMC and a non-ionic hydrophilic polymer (discussed hereinbelow)preferably are present in a weight ratio of HPMC: non-ionic polymer ofabout 10:1 to about 3:1, more preferably 7:1 to 5:1, most preferably6:1.

Whereas HPMC is a useful excipient to ensure sustained release offluvastatin from an oral dosage form, applicant has found thatconventional sustained release formulations containing HPMC alone as therate-modifying excipient may nevertheless exhibit an initial drug burstor premature release of fluvastatin. By “premature release” is meantthat a substantial amount of fluvastatin may be released in a shortperiod of time after ingestion such that the amount of active agentdelivered to the site of action is above the therapeutic level. Whereasthis may not have any consequence for the efficacy of the drug substancethere may be resultant toxic side effects associated with the greaterthan therapeutic dose. Surprisingly the applicant has discovered thatthe premature release may be avoided or ameliorated if the oral dosageform additionally comprises at least one non-ionic hydrophilic polymer.

Non-ionic hydrophilic polymers used in oral dosage forms according tothe invention may be selected from the group consisting ofhydroxyethylcellulose (HEC) having a number average molecular weight offrom 90,000 to 1,300,000, preferably about 1,000,000 to about 1,300,000;hydroxypropyl cellulose (HPC) having a number average molecular weightof 370,000 to 1,500,000, preferably 850,000 to 1,500,000, morepreferably 1,000,000 to 1,200,000 and poly(ethylene)oxide (PEO) having anumber average molecular weight of about 100,000 to 500,000, preferably150,000 to 300,000, more preferably 200,000.

Examples of HEC polymers are commercially available from HerculesIncorporated, Aqualon Division under the tradename NATROSOL 250H orNATROSOL 250L. Examples of HPC polymers are also available from HerculesIncorporation, Aqualon Division under the tradename KLUCEL or KLUCELHXF, and examples of PEO polymers are available from Union CarbideCorporation under the tradename POLYOX. Methods of making the non-ionichydrophilic polymers heretofore described are known to those skilled inthe art. The non-ionic hydrophilic polymers may be employed in oraldosage forms according to the invention in amounts ranging from about 1to about 20% by weight, preferably about 3 to 12% by weight, morepreferably about 4 to 7% by weight based on the total weight of the oraldosage form. The non-ionic hydrophilic polymer is present in an amountsufficient to prevent premature release of fluvastatin.

Oral dosage forms according to the invention may comprise otherexcipients which serve to facilitate processing and/or provide enhancedproperties of the oral dosage forms, including well known tablettingexcipients such as binders, e.g gelatin, sugars, natural and syntheticgums, polyvinylpyrollidone), disintegrants (e.g. crosscarmelose,crospovidone, sodium starch glycolate), lubricants (e.g., magnesiumstearate, hydrogenated vegetable oils, carnauba wax), flow agents (e.g.silicon dioxide), anti-adherents or glidants (e.g. talc) as well assweeteners, fillers, flavourants and antioxidants.

As fluvastatin is sensitive to acidic media, it is conventional toinclude a basifying agent to impart a pH of at least about 9. Anybasifying agent known for stabiliising formulations containing HMG CoAreductase inhibitors may be employed. Applicant has surprisingly foundthat in oral dosage forms comprising a typical basifying agent, e.g.potassium carbonate or bicarbonate, and polyvinylpyrollidone andfluvastatin, there is a tendency for discolouration during storage. Thisdiscolouration, in the form of dark spots, is distinct from thathereinabove described and is thought to be a result of the action of insitu-generated carbonic acid on the active agent or excipients (thecarbonic acid being formed as a degradation product of the potassiumcarbonate or bicarbonate in the presence of PVP and ambient moisture).In keeping with the discolouration associated with the HPMC, thisdiscolouration does not affect the safety and efficacy of the oraldosage forms and is likewise masked by adopting the same precautions ashereinabove described.

Whereas the oral dosage forms described hereinabove are used toadminister fluvastatin, they may be employed to deliver other HMG CoAreductase inhibitors such as simvastatin, pravastatin, lovastatin,atorvastatin and cerivastatin. The HMG CoA reductase inhibitors may beused in their free-acid forms, their ester forms, e.g. lactone forms oras pharmaceutically acceptable salts, e.g sodium salts.

The structure and method of manufacture of fluvastatin is disclosed inEuropean patent applications EP-A-114 027 and EP-A-547 000, which areincorporated herein by reference.

Oral dosage forms according to the invention may be manufacturedaccording to any of the procedures known in the art. In the case oftablets they may be formed by a process which forms another aspect ofthis invention and which comprises the step of an aqueous highsheargranulation of the active agent and the tabletting excipients.

Granules are produced in a manner known per se, for example usingaqueous granulation methods known for the production of “built-up”granules or “broken-down” granules.

Methods for the formation of built-up granules operate continuously andcomprise, for example, simultaneously spraying the granulation mass withgranulation solution and drying, for example in a drum granulator, inpan granulators, on disc granulators, in a fluidised bed, byspray-drying or spray-solidifying, or operate discontinuously, forexample in a fluidised bed, in a batch mixer or in a spray-drying drum.

Preferred are methods for the production of broken-own granules, whichcan be carried out discontinuously and in which the granulation massfirst forms a wet aggregate with the granulation solution, whichaggregate is then comminuted or formed into granules of the desiredparticle size using known granulation methods, the granules then beingdried. Suitable granulators include, for example an Alexandergranulator.

The granulation mass consists of comminuted, preferably ground, activeingredient and the excipients mentioned above. Depending on the methodused, the granulation mass may be in the form of a premix or may beobtained by mixing the active ingredient into one or more excipients ormixing the excipients into the active ingredient. The wet granules arepreferably dried, for example in the described manner by spray drying orin a fluidised bed.

Compression to form tablet cores may be carried out in conventionaltabletting machines, for example EK-0 Korsch eccentric tablettingmachines. The tablet cores may be of various shapes, for example round,oval, oblong, cylindrical etc., and various sizes, depending on theamount of active ingredient employed.

There now follows a series of example which serve to illustrate theinvention.

EXAMPLE 1

A portion of fluvastatin sodium is calculated and weighed. Potassiumbicarbonate, microcrystalline cellulose, povidone, HPC, and HPMC areweighed and placed into individual separately labelled containers. A 20weight percent excess of the batch quantity of OPADRY Yellow,YS-1-6347-G, is then placed into a labelled container. Themicrocrystalline cellulose, fluvastatin sodium, povidone, HPC, and HPMCare transferred, in that order, into a collette gral and mixed for 5minutes with the plow at slow speed and the chopper off. The resultingmixture is passed through a 0.033 inch screen using a tornado mill withknives forward and at a slow speed. The screened material is then mixedagain in a collette gral with the plow at slow speed and the chopperoff.

Potassium bicarbonate is dissolved into purified water until a clearhomogenous solution is obtained. The potassium bicarbonate solution isthen combined with the screened material, and the resulting mixture isgranulated in a collette gral with the plow at fast speed and thechopper at slow speed. After adding the above solution, granulationshould continue for 30 seconds with the plow at fast speed and thechopper at slow speed and for another 30 seconds with the plow at fastspeed and the chopper at fast speed. The granulated mixture is thendried in a fluid bed dryer using a target inlet temperature of 50degrees C until an LOD of 2 percent to 3 percent is obtained.

The dried granules are then passed through a {fraction (1/16)} inchscreen using a tornado mill with knives forward and at slow speed. Anamount of magnesium stearate based on the proportion of actual yieldfrom the {fraction (1/16)} inch screening step to the theoretical yieldfrom the same step is calculated and weighed. The weighed magnesiumstearate is then passed through a 60 mesh screen and blended with thedried granules in a free fall blender and the resulting granulationblend discharged into a plastic lined labelled drum. The granulationblend is then compressed into tablets and the tablets are dedusted,passed through a metal checker, and stored in a plastic, labelled drum.

To coat the tablets, the OPADRY Yellow is mixed with a required quantityof purified water to obtain a 10 w/w percent suspension. The tablets aretransferred to a coating pan and warmed to a temperature of 40-45degrees C. The OPADRY Yellow suspension is then added, to spray coat thetablets until a 3 percent solid weight gain per tablet is achieved. Thecoating spray is shut off, and the tablets are cooled by shutting offthe pan heat and jogging the pan for 5 minutes.

EXAMPLE 2

84.24 mg of fluvastatin sodium were combined with the followingexcipients according to the method described in Example 1 to provide asingle dosage form described in Table 1:

TABLE 1 Fluvastatin sodium 84.24 mg  Potassium bicarbonate, USP 8.42 mgMicrocrystalline cellulose, NF, PHI 0 1 111.26 mg  (AVICEL). PovidoneUSP 4.88 mg HPC, NF (KLUCEL HXF) 16.25 mg  HPMC, USP (METHOCEL K 100LV)97.50 mg  Magnesium Staerate 2.44 mg OPADRY Yellow 9.75 mg

The OPADRY yellow consisted of HPMC 2910 3cps (72% ww); titanium dioxide(21.413% ww); PEG 8000 (4.0% ww); and iron oxide yellow (2.587% ww) (24%oxides TiO₂+FeO₂).

The formulation of Table 1 produced oral dosage forms which showed nosign of the mottled discolouration.

When the OPADRY yellow consisted of HPMC 2910 3cps (80% ww); titaniumdioxide (14.080% ww); PEG 8000 (4.0% ww); and iron oxide yellow (1.920%ww) (16% oxides TiO₂+FeO₂), the oral dosage forms displayed a mottled,uneven discolouration.

What is claimed is:
 1. A color-stable sustained release tabletcomprising granules comprising fluvastatin and a hydroxypropyl methylcellulose polymer; wherein the granules have a mean particle size ofless than 200 microns; and the hydroxypropyl methyl cellulose polymercomprises up to 12 percent hydroxypropyl functionality, has a numberaverage molecular weight of about 20,000 to about 170,000, and ispresent in an amount of from 15 to 50 weight percent, based on the totalweight of the composition.
 2. The tablet according to claim 1 whereinthe granules have a mean particle size of less than 125 microns.
 3. Thetablet according to claim 1 wherein the granules have a mean particlesize of 100 to 125 microns.
 4. The tablet according to claim 1 whereinthe hydroxypropyl methyl cellulose polymer comprises from 7 to 12percent hydroxypropyl functionality.
 5. The tablet according to claim 1wherein the hydroxypropyl methyl cellulose polymer has a normalviscosity of 100 to 100,000 centipoise as determined at a concentrationof 2.0 weight percent of polymer in water.
 6. The tablet according toclaim 1 wherein the hydroxypropyl methyl cellulose polymer has a numberaverage molecular weight of 20,000 to 30,000.
 7. A color-stablesustained release tablet comprising granules comprising fluvastatin, ahydroxypropyl methyl cellulose polymer, a coating material, and acoloring agent; wherein the coloring agent is present in an amount ofless than or equal to 73 weight percent, based on the total weight ofthe coating; and the hydroxypropyl methyl cellulose polymer comprises upto 12 percent hydroxypropyl functionality, has a number averagemolecular weight of about 20,000 to about 170,000, and is present in anamount of from 15 to 50 weight percent, based on the total weight of thecomposition.
 8. The tablet according to claim 7 wherein the coloringagent is present in an amount of 17 to 30 weight percent.
 9. The tabletaccording to claim 8 wherein the coloring agent is present in an amountof 22 to 25 weight percent.
 10. The tablet according to claim 7 whereinthe coloring agent is selected from the group consisting of titaniumdioxide, iron oxide, and combinations thereof.
 11. The tablet accordingto claim 7 wherein the coloring agent is a combination of titaniumdioxide and iron (II) oxide.
 12. The tablet according to claim 7 whereinthe tablet additionally comprises a non-ionic hydrophilic polymerselected from the group consisting of hydroxyethyl cellulose,hydroxypropyl cellulose, poly(ethylene)oxide, and combinations thereof.13. The tablet according to claim 12 wherein the ratio of thehydroxypropyl methyl cellulose polymer to non-ionic hydrophilic polymeris from about 10:1 to 3:1.
 14. The tablet according to claim 13 whereinthe ratio of the hydroxypropyl methyl cellulose polymer to non-ionichydrophilic polymer is from 7:1 to 5:1.
 15. The tablet according toclaim 13 wherein the ratio of the hydroxypropyl methyl cellulose polymerto non-ionic hydrophilic polymer is about 6.1.
 16. The tablet accordingto claim 12 wherein the hydroxyethyl cellulose has a number averagemolecular weight of from 90,000 to 1,300,000.
 17. The tablet accordingto claim 12 wherein the hydroxypropyl cellulose has a number averagemolecular weight of from 370,000 to 1,500,000.
 18. The tablet accordingto claim 12 wherein the poly(ethylene)oxide has a number averagemolecular weight of from 100,000 to 500,000.
 19. The tablet according toclaim 12 wherein the non-ionic hydrophilic polymer is present in thetablet in an amount of from 1 to 20 weight percent, based on the totalweight of the tablet.
 20. The tablet according to claim 19 wherein thenon-ionic hydrophilic polymer is present in the tablet in an amount offrom 3 to 12 weight percent.
 21. A method for preparing a color-stablesustained release oral dosage pharmaceutical composition comprisingfluvastatin and a hydroxypropyl methyl cellulose polymer, said methodcomprising storing the composition at a relative humidity not exceeding75% and at a temperature of 25° C. to 40° C., wherein said methodprevents or reduces the formation of gel in the hydroxypropyl methylcellulose polymer.
 22. The method according to claim 21 wherein thecomposition is stored at a relative humidity not exceeding 60%.
 23. Themethod according to claim 21 wherein the composition is formed ofcompressed granules.
 24. The method according to claim 23 wherein thegranules have a mean particle size of less than 200 microns.
 25. Themethod according to claim 24 wherein the granules have a mean particlesize of less than 125 microns.
 26. The method according to claim 21wherein the granules have a mean particle size of 100 to 125 microns.27. The method according to claim 21 wherein the hydroxypropyl methylcellulose polymer comprises up to 12 percent hydroxypropylfunctionalityand has a number average molecular weight of about 20,000 to about170,000.
 28. The method according to claim 22 wherein the hydroxypropylmethyl cellulose polymer is present in amounts of from 15 to 50% byweight.
 29. The method according to claim 21 wherein the compositionadditionally comprises a non-ionic hydrophilic polymer selected from thegroup consisting of hydroxyethyl cellulose, hydroxypropyl cellulose,poly(ethylene)oxide, and combinations thereof.
 30. The method accordingto claim 29 wherein the ratio of the hydroxypropyl methyl cellulosepolymer to non-ionic hydrophilic polymer is from about 10:1 to 3:1.